GAMMA-AMINOBUTYRIC ACID AND GLUTAMIC ACID IN HUNTINGTON'S DISEASE: INVESTIGATION OF NEUROTRANSMITTER RECEPTORS USING RADIOLABELED AGONISTS by-

3H-Muscimol, a structural analog of y-aminobutyric acid (GABA) , binds to rat brain synaptic membranes in a saturable manner, with a high affinity dissociation constant of 2.2 nM. Binding is increased in membranes that have been treated with Triton X-1Q0 and is not 3 dependent upon sodium. High affinity H-muscimol binding is regionally distributed, with highest binding density in the cerebellum > cerebral cortex > hippocampus, brainstem, midbrain, hypothalamus > pons-medulla, 3 spinal cord. H-Muscimol binding is most highly concentrated in the synaptic membrane fraction. These properties are consistent with those 3 reported for sodium-independent H-GABA binding to brain GABA receptors. Muscimol is displaced from synaptic membranes only by compounds which interact in neurophysiological studies with GABA receptors, indicating that the effects of muscimol result from activation of GABA receptors. ^H-Kainic acid, a structural analogof L-glutamic acid, binds to rat brain membranes in a saturable manner with a dissociation 3 constant of 5 nM. H-Kainic acid binding is regionally distributed with highest density in the striatum > hippocampus > cerebellum, 3 cerebral cortex > midbrain, pons-medulla. H-Kainic acid is displaced potently by L-glutamate (IĈ 0 = 0.12 p,M), although physiological antagonists of L-rglutamate-induced excitations are ineffective at inhibiting ^H-kainic acid binding. Compounds related to L-aspartic acid 3 are also very weak inhibitors of H-kainic acid binding, suggesting that x xi excitatory amino acid receptors exist that are distinct from the sites mediating kainic acid-induced depolarizations. Several cations 3 effectively displace H-kainic acid binding, divalent cations being more potent in this respect than monovalent cations. Injection of kainic acid into the rat striatum has been shown to produce alterations that are neurochemically and histologically similar to those occurring in Huntington’s Disease (HD), as intrinsic striatal neurons are destroyed while afferent terminals and axons of passage are unaffected. Following kainic acid lesion, ^H-kainic acid binding undergoes a slow decrease over a period of 48 days. At 30 days after lesion, ^H-muscimol binding density in lesioned striatum is not significantly different than in control striatum. These results indi­ cate that.kainic acid binding sites are located on neurons originating in the striatum, while striatal GABA receptors appear to be localized on endings of neuronal afferents originating outside the striatum of on glia. 3 3 The density of H-kainic acid and H-muscimol binding was 3 determined an regions of HD and control human brains. H-Kainic acid binding density is significantly reduced from control in HD caudate nucleus (-55%) and putamen (-53%), but not in HD cerebellum, frontal cortex, or globus pallidus. ^H-Muscimol binding density, determined using brain membranes that had been treated with Triton X-100 to remove endogenous inhibitors of GABA receptor binding, was significantly decreased compared to control in HD caudate nucleus (-36%) and putamen (-33%) but not in HD frontal cortex.